We have undertaken a "candidate" gene approach to search for gene(s) predisposing for insulin resistance and NIDDM in the Pima Indians. During a screening (by sib-pair linkage analysis) of polymorphic markers at selected candidates, we have found evidence for a possible linkage of the gene for skeletal muscle glycogen synthase (GYS) on chromosome 19q with fasting insulin and with measures of insulin action in-vivo. Detailed comparative analysis of GYS mRNA and protein levels in skeletal muscle of insulin sensitive and resistant Pimas revealed a 30% reduction of the protein in the latter group. In contrast, no differences in mRNA could be detected between the two groups. Because this phenomenon could be caused by a decrease in the stability of the protein due to amino acid substitution(s), analyses comparing GYS coding sequences and enzymatic activity between insulin sensitive and resistant subjects are in progress.